14.02.2024

SCN5A variants in left ventricular noncompaction cardiomyopathy

Left ventricular noncompaction cardiomyopathy (LVNC) poses significant challenges in clinical management due to its association with arrhythmias and heart failure. The underlying molecular mechanisms of ventricular arrhythmias in LVNC patients remain elusive, and there is no special treatment for LVNC. Some previous studies have pointed out that mutations or abnormalities in the SCN5A gene (encoding for the voltage-gated sodium channel Nav1.5) may increase arrhythmia susceptibility in LVNC. Nevertheless, the nature of these SCN5A mutations and the mechanisms through which they may contribute to the development of arrhythmias in LVNC patients have yet to be fully elucidated.

A recent study sheds light on the SCN5A mutations in LVNC and their impact on cardiomyocyte excitability and contractility. Researchers collected myocardial samples from LVNC patients undergoing heart transplantation and conducted exome sequencing to identify SCN5A variants. Approximately half of the LVNC patients carried SCN5A variants previously linked to ventricular arrhythmias. Notably, all LVNC patients with these SCN5A variants exhibited clinical manifestations of arrhythmias.

Functional analyses demonstrated that all identified SCN5A variants exhibited gain-of-function properties, with increased channel activation and enhanced fast inactivation. In human embryonic stem cell-derived cardiomyocytes (hESC-CMs), SCN5A mutations led to increased contractility and arrhythmia-like fibrillation (measured with the CardioExcyte 96 system). Treatment with lidocaine effectively rescued or alleviated fibrillation, highlighting the therapeutic potential of targeting sodium ion channels.

Importantly, the adenovirus-mediated transfection allowed for the efficient delivery of SCN5A variants into hESC-CMs, enabling the recapitulation of disease-relevant phenotypes in vitro. This approach provides a valuable tool for studying the functional consequences of SCN5A mutations and screening potential therapeutic agents in a controlled laboratory setting.

In summary, this study suggests that SCN5A mutations play a significant role in conferring arrhythmia susceptibility in LVNC patients. Furthermore, it advocates for the use of cardiomyocyte models harboring these mutations for drug screening purposes, aiming to develop targeted therapies not only for LVNC but also for other arrhythmia disorders.

Find the original article here: https://www.sciencedirect.com/science/article/pii/S2405580824000177

Learn more about combined contractility, electrophysiology and cell viability measurements with the CardioExcyte 96 system: https://www.nanion.de/products/cardioexcyte-96/